Emerging Therapies The Candins

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Emerging TherapiesThe Candins

• John H. Rex, M.D.
• University of Texas Medical School
• Houston, Texas

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Disclaimer

• AB Biodisk
• Aronex Pharmaceuticals
• Bristol-Myers Squibb
• Fujisawa
• Gilead Sciences
• Janssen Pharmaceutica
• Lilly Pharmaceuticals

• Merck Research Laboratories
• Ortho-Biotech
• Pfizer, Inc.
• Schering-Plough Research Institute
• The Liposome Company
• Versicor

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The Fungal Cell Wall

• A promising target

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The Amazing Fungal Cell Wall

• Hard to study
• Isozymes
• Hard to purify
• Good targets?
• Glucan
• Chitin

Graphic courtesy of Myra Kurtz, PhD, Merck
Research Laboratories
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Glucan Synthesis Inhibitors

• Echinocandins Papulacandins
• Cyclic hexapeptide Glycolipids
• N-linked lipid side-chain
• Others compound classes are active Onishi et al,
  AAC 44368, 2000

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Echinocandin Nomenclature

• Echinocandins
• Technical has an echinocandin B nucleus
• Common usage
• Echinocandin B derivatives
• Pneumocandins modified echinocandin nucleus
• Papulacandins
• For this talk
• Will use echinocandin to refer to both
  echinocandins and pneumocandins

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Echinocandin Mechanism of Action

• Data are limited by lack of pure enzyme
• Best guess Inhibits glucan synthase
• But, is not a competitive inhibitor
• Glucan synthase genes are complex
• Three genes in Saccharomyces FKS1, 2, 3
• FKS1 is cell-cycle regulated vegetative
• FKS2 requires calcineurin for expression
• FK506 ? blocks calcineurin ? decreases FKS2
• FKS3 is not well understood at present

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Mechanism of Action Predictions

• Cell wall synthesis is vital distinctive
• This is penicillin for fungi should be lethal
• Should work even if resistant to other drugs
• Less beta-glucan ? less susceptible
• Crypto is mostly a- (1-3), a-(1-6) is resistant
• Pneumocystis carinii uses beta-glucan
• Pneumocandins so named in part due to proven
  activity against P. carinii
• Is another proof of P. cariniis fungal affinity

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The Drugs
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Cilofungin

• This was the first real try
• Studied in the late 1980s
• Promising activity
• Major solubility problems
• Only IV, toxic carrier required
• Drug was abandoned
• Spectrum was also somewhat limited

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But, Now We Have

• Three serious contenders
• Caspofungin (MK-991, CancidasTM) from Merck
• FK463 from Fujisawa
• VER-002 (V-Candin, LY303366) from Versicor
• All are well underway
• Will try to draw examples from all three drugs
• Generally, results are similar for the three
• More data available on caspofungin than others

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General Characteristics

• Pharmacology
• Poor PO bioavailability probably always IV
• Good water solubility, no need for a carrier
• Largely metabolized, minimal renal clearance
• No dose adjustment for renal failure
• Long half-lives, single daily dosing possible
• Excellent safety profiles in animals man
• ? Interaction w/ CsA. Caspo, at least, may cause
  ? LFTs with CsA. FK506 is OK. Mechanism unknown.

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In vitro Activity Candida

• VER-002 MIC90 in RPMI Pfaller, AAC 41763, 1997
• C. albicans 0.12
• C. glabrata 0.25
• C. tropicalis 0.25
• C. krusei 0.25
• C. parapsilosis 2 Some ? is typical
• No cross-R with azoles or amphotericin B
• Often cidal Ernst, DMID 3375, 99 Klepser AAC
  421387, 98
• Precise result is media and isolate dependent

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In vitro Activity Aspergillus
Growth Control Increasing Concentration of
Echinocandin
Healthy Happy
Point of Transition MEC, or Minimum
Effective Concentration
Stubby Aberrant Sick
Photomicrographs and definition of MEC Kurtz et
al., AAC 381480, 1994
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In vitro Activity Aspergillus Others

• Caspofungin MECs (mg/ml)
• Aspergillus fumigatus 0.5
• Other Aspergillus spp. 0.5
• Pseudallescheria boydii 0.5-4
• Fusarium solani/oxysporum 16
• Rhizopus arrhizus 16
• Blastomyces, Histoplasma 0.5-8
• Sporothrix schenckii 1-16
• Arkan, ICAAC 99, J-160 Espinel-Ingroff AAC
  362950, 1999

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In vivo Activity Candida

• FK463, murine model, cyclophosphamide
• Survival ED50 (mg/kg/d) FK463 Fluco
• C. albicans 0.14 2.15
• C. tropicalis 0.28 3.71
• C. glabrata 0.30 6.27
• C. krusei 0.77 9.52
• C. parapsilosis 1.00 10.9
• 2 log ? tissue CFU/g
• Ikeda et al., AAC 44 614, 2000

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In vivo Activity Aspergillus

• VER-002, murine model, cyclophosphamide
• Model produced transient neutropenia
• IV infection with Aspergillus conidia
• Lung CFU/g Survivors
• Control 3.1 x 102 0/10
• Ampho 2 mg/kg/d 0.9 x 102 7/10
• VER-002 10 mg/kg/d 0.6 x 102 8/10
• Verweij et al., AAC 42873, 1998

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In vivo Activity Aspergillus

• Rabbit model, Ara-C, persistent neutropenia
• VER-002, intratracheal inoculation

AmB, 1 mg/kg/d 1.5 log ? CFU/g 8.0 d survival
Control lung section 6.5 d survival
VER-002, 10 mg/kg/d No ? CFU/g 10.5 d survival
Petraitis et al., AAC 422898, 1998
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Understanding Aspergillus

• Candins are cidal for the growing tips and some
  interior cells
• Static, non-growing interior cells are not killed
• Fragmentation due to death of interior cells may
  increase apparent CFU!

Visible Light
Stain only the viable fungal segments
Douglas CM et al. ICAAC 2000, Abstract 1683
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Aspergillus Summary

• In vitro
• Growth inhibition, but not entirely lethal
• In vivo
• Definite effects on survival
• Tissue CFU/g effects are inaccurate
• Aspergillus CFU dont reflect biomass well
• All data taken together
• Cidal on growing portions. Even a little help
  from the host will permit clearance.

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Combinations for Aspergillus?

• ICAAC 932, Arikan et al. In vitro
• Caspo amB Synergistic for Aspergillus
• Also for Fusarium, despite lack of activity
  alone!
• ICAAC 1685, Nakajima et al. In vivo
• FK463AmB, murine model, combo was best
• ICAAC 1686, Kohno et al. In vivo
• FK463AmB, murine model, combo was best
• P lt 0.001 noted for ? fungal burden by combo
• Paralleled serologic galactomannan marker

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Clinical Data

• Candidiasis

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OPC and Esophagitis

• Caspofungin has now reported two studies
• Sable, ICAAC 97, LB-33. Arathoon IDSA 98, 99
• Dose ranging, randomized vs. amphotericin B
• Total N gt 200, CD4 mostly lt 50
• Cure rate 80, same as ampho
• FK463 (Pettengell, ICAAC 2000 1104)
• Open label series with candidal esophagitis
• 97 cureimprove rate (scoring rules less
  stringent than for caspo)

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A Picture is Worth A Lot
This AIDS patient failed everything fluco,
(lipid) ampho. The only thing that helped even a
little was chewing itraconazole capsules.
Before Candin
After Candin
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Studies Underway

• Caspofungin
• Randomized study vs. fluco for esophagitis
• Invasive candidiasis (mixture of blood stream and
  non-bloodstream)
• Other drugs
• Fewer public details
• Similar datasets seem likely

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Clinical Data

• Aspergillosis

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Salvage Therapy for IA

• Maertens et al., ICAAC 2000, 1103
• Proven IA, refractory or intolerant of usual tx
• Refractory (80) required 1 week of other therapy
• Favorable response (CR/PR) required radiographic
  improvement, judged by panel
• Patients 45 who were refractory, 9 intolerant
• Caspo at 70 mg/d for 1-160 d
• 41 CR/PR. Response by site...
• 45 lung, 50 single organ, 20 disseminated

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Reference Aspergillosis Cohort

• Data courtesy John Hiemenz
• Historical cohort of 206 patients
• Similar mix of underlying diseases and sites of
  aspergillosis to salvage therapy patients
• Cohort chosen because they got at least one week
  of standard therapy
• Cohort CR/PR rate 17
• Still less than caspo, even when adjusted for
  site of IA, neutropenia, BMT, and/or steroid use

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More Aspergillosis Context

• Data alert! Scoring rules vary!
• Voriconazole salvage (IDSA 304)
• 88 refractory, 41 (21/51) CR/PR by ITT
• Liposomal nystatin (ICAAC 1102)
• 83 refractory, 25 (6/19) CR/PR by ITT
• Posaconazole (ICAAC 1109)
• 66 were refractory, 32 (8/25) CR/PR by ITT

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Summary
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The Candins Show Great Promise

• Candida
• Activity is excellent and easily shown
• Aspergillus
• Harder to assess. In vitro-in vivo disconnect.
• But, clinical data are promising
• Combinations are very intriguing
• Other moulds
• Even more difficult to assess. Activity varies
  with species and conditions.

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Thank You!

• Its tough to make predictions, especially about
  the future
• Yogi Berra